Is codeine (opioid) effective for treating restless legs syndrome (RLS)?

Codeine for Restless Legs Syndrome

Codeine and other opioids should be considered as second-line therapy for severe to very severe restless legs syndrome (RLS) that is refractory to first-line treatments, not as a standard first-line approach. 1, 2

Treatment Algorithm for RLS

First-Line Treatments

1. Alpha-2-delta ligands (pregabalin or gabapentin)

   • Recommended as first-line due to strong efficacy and favorable long-term safety profile 2
   • Particularly appropriate for patients with chronic kidney disease with dose adjustment 2

2. Iron therapy

   • Indicated when ferritin ≤75 ng/mL or transferrin saturation <20% 2
   • Options include:
     • Oral ferrous sulfate for most patients
     • IV ferric carboxymaltose for inadequate response to oral iron
     • IV iron sucrose for ESRD patients with ferritin <200 ng/mL and transferrin saturation <20% 2

Second-Line Treatments

1. Opioids (including codeine)

   • Indicated for:
     • Severe to very severe RLS inadequately controlled by previous treatments 1, 3
     • Patients who have failed dopaminergic agents or alpha-2-delta ligands 3
   • Effective doses are considerably lower than those used for chronic pain 3
   • Common opioids used for RLS:
     • Oxycodone (10-30 mg daily)
     • Methadone (5-20 mg daily)
     • Codeine, tramadol, morphine, and hydrocodone are also options 3

2. Dopamine agonists (pramipexole, ropinirole, rotigotine)

   • The AASM suggests against standard use due to risk of augmentation 1, 2
   • May be used short-term in patients who prioritize symptom reduction over long-term adverse effects 1

Evidence for Opioids in RLS

The American Academy of Sleep Medicine suggests the use of extended-release oxycodone and other opioids (including codeine) over no opioids for RLS with moderate certainty of evidence 1. This recommendation is based on:

• Clinical trials demonstrating significant improvement in disease severity with moderate effect size 1
• Effectiveness in treating refractory RLS symptoms 3, 4
• Particular utility in patients with severe symptoms unresponsive to other treatments 5

A Cochrane review found that opioids seem effective for treating RLS symptoms, with the major adverse events being gastrointestinal problems, fatigue, and headache 6.

Important Considerations for Opioid Use in RLS

Benefits

• Effective for symptom control in refractory cases 3
• Lower doses required compared to pain management 3
• No risk of augmentation (unlike dopaminergic agents) 4

Risks and Monitoring

• Adverse effects include fatigue, somnolence, dizziness, constipation, nausea, and headache 1, 4
• Risk of abuse, chemical dependence, and overdose 1
• Requires:
  • Assessment of opioid risk with standard questionnaires
  • Opioid treatment agreement
  • Urine drug screens
  • Consultation of prescription drug monitoring programs
  • Frequent reevaluation of effectiveness and side effects 3

Clinical Pearls

• Controlled-release medication should be used for evening dosage and short-acting drugs (if needed) during the day 3
• The risk of opioid use disorder appears relatively low at the doses used for RLS 3
• Opioids may be particularly valuable for treating dopaminergic augmentation 2
• Before initiating opioids, ensure all treatable causes of RLS refractoriness (such as low iron stores) have been addressed 3

In summary, while codeine and other opioids are effective for RLS, they should be reserved for patients with severe symptoms who have failed first-line treatments due to their potential risks.